This application is a 371 of PCT/GB00/01294 filed Apr. 4, 2000.
This invention relates to novel compounds having pharmaceutical properties.
Certain aminoalkyl bicycloheptanes having a pharmacological effect on the central nervous system, are disclosed in British Patent 1 586 249. Also, British Patents 1 444 717 and 1 549 174 describe aminoalkyl bicyclooctyl derivatives with similar properties.
The compounds of the invention are of the following formula: 
in which R1 and R2 are each hydrogen or C1-4 alkyl, or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 C1-4 alkyl substituents,
R3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2;
or a salt or ester thereof.
The compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
In the above formula (I), R1 and R2 are preferably hydrogen or C1-4 alkyl.
A C1-4 alkyl group can be methyl, ethyl, or propyl, and can be branched or unbranched and includes isopropyl and tert. butyl. Preferably R1 and R2 are each hydrogen, methyl or ethyl, and especially hydrogen or methyl. The xe2x80x94NR1R2 group is most preferably xe2x80x94N(CH3)2 or xe2x80x94NH(CH3).
Compounds of formula (I) are preferably bicycloheptyl derivatives (n is 1).
The R3 substituent is attached to the bicyclo ring at certain positions on the substituent, and examples of R3 groups are a-naphthyl, xcex2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, 2-, 3-, 5- or 6-benzofuranyl, 2- or 5-benzothiazolyl, 2-, 3-, 6- or 7-quinolinyl or 3-, 6- or 7-isoquinolinyl. A naphthyl group is preferably xcex2-naphthyl. Preferred R3 substituents are xcex2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl and 2-, 3-, 5- or 6-benzofuranyl.
The R3 group can also be substituted, substitution being in one or both rings, with one or more, preferably 1 to 3, substituents. Preferred substituents include C1-4 alkyl, C1-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, xe2x80x94NRxe2x80x2Rxe2x80x3 and xe2x80x94CONRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are each hydrogen or C1-4 alkyl.
A preferred value of R3 is optionally substituted xcex2-naphthyl, and especially unsubstituted xcex2-naphthyl.
A further preferred value of R3 is optionally substituted 2-, 3-,5- or 6-benzothienyl.
As indicated above, it is possible to prepare salts of the compound of the invention and such salts are included in the invention. Such salts are preferably the pharmaceutically acceptable, non-toxic salts. Of special interest are acid addition salts, in particular those with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
It will be appreciated that when a substituent on an R3 group is acidic such as, for example, a carboxy group, the opportunity exists for esters. These can be aliphatic or aromatic, being preferably alkyl esters derived from C1-4 alkanols, especially methyl and ethyl esters. An example of an ester substituent is xe2x80x94COORxe2x80x2 where Rxe2x80x2 is C1-4 alkyl.
The compounds of the invention contain asymmetric carbon atoms as indicated by asterisks in the following structures: 
This asymmetry gives rise to cis- and trans-isomers as well as, in the case of the bicycloheptyl derivatives, exo- and endo-forms. Thus the bicycloheptyl derivatives exist as trans exo, trans endo, cis exo and cis endo forms, and in each instance R and S enantiomers. In the case of the bicyclooctyl derivatives, there are cis and trans derivatives only, each of which exist in R and S enantiomeric form. The compounds can be prepared as racemic mixtures and can conveniently be used a such, but individual isomers can be isolated by conventional techniques, or are preferably prepared by chiro-selective methods. Both racemic mixtures and individual isomers are included in the present invention.
A preferred group of compounds of formula (I) above is one in which R1 and R2 are each hydrogen or C1-4 alkyl, and R3 is optionally substituted xcex2-naphthyl.
A further preferred group of compounds of formula (I) is one in which R1 and R2 are each hydrogen or C1-4 alkyl, and R3 is optionally substituted benzothienyl.
A preferred group of compounds of the invention can be represented as follows: 
in which R1 and R2 are each hydrogen or C1-4 alkyl, R4 and R5 are each C1-4 alkyl, C1-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, xe2x80x94NRxe2x80x2Rxe2x80x3 or xe2x80x94CONRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are each hydrogen or C1-4 alkyl, and p and q are each 0 or 1 to 3, such that the sum of p and q is preferably 0 or 1 to 3; or a salt thereof. When the naphthyl group is substituted there is preferably a single substituent at the 6-position. Of the above compounds of formula (Ia), the most preferred are the unsubstituted compounds in which p and q are both 0, and furthermore the compounds in which n is 1, the bicycloheptyl derivatives, are most preferred.
A further preferred group of compounds of the invention can be represented as follows: 
in which R1 and R2 are each hydrogen or C1-4 alkyl, and R6 is C1-4 alkyl, C1-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, xe2x80x94NR Rxe2x80x3 or xe2x80x94CONRxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are each hydrogen or C1-4 alkyl, and p is 0 or 1 to 3; or a salt thereof. When p is 2 or 3, the substituents can be different.
A further preferred group of compounds of the invention can be represented as follows: 
where the bicyclo group is attached at the 5- or 6-position, and in which R1 and R2 are each hydrogen or C1-4 alkyl, and R6 is C1-4 alkyl, C1-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, xe2x80x94NRRxe2x80x2Rxe2x80x3 or xe2x80x94CONRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are each hydrogen or C1-4 alkyl, and p is 0, 1 or 2; or a salt thereof. When p is 2, the substituents can be different.
As examples of compounds of the invention, and their pharmaceutically acceptable salts, in isomeric or racemic form, there are included:
N,N-Dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine
N-Methyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine
[(3-(6-Methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1H-Indol-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-2-naphthylbicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-7-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamnine
[3-(1-Benzothien-4-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(1-Benzothien-6-yl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethylmethanamine
[3-(3-Methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Fluoro-1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
N,N-Dimethyl-[3-(2-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine
N,N-Dimethyl-[3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine
[3-(2-Ethyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethylmethanamine
[3-(2-Fluoro-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(3-Bromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethylmethanamine
[3-(2,3-Dibromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine
[3-(6-Methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine
[3-(1-Benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine
[3-(1-Benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine
[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine
[3-(6-Fluoro-2-naphthyl) bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine
N-Methyl-[3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine
1-{[3-(3-Methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine
1-{[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine
1-{[3-(3-Methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine
6-{[3-[(Dimethylamino)methyl]bicyclo[2.2.1]hept-2-yl}-2-naphthol
(3-Naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine
[3-(6-Methoxy-2-naphthyl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine
[3-(1H-Indol-3-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine
N,N-dimethyl-[3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine
[3-(1-Benzothien-5-yl)bicyclo[2.2-2]oct-2-yl]-N,N-dimethylmethanamine
[3-(1H-indol-5-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine
N-methyl-[3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine
The invention also includes processes for the production of compounds of the formula (I) above by any of the well known methods for preparing substituted alkyl amines. For example, they can be made from intermediates of the formula: 
where R3 and n have the values given above, and R7 is xe2x80x94CN, xe2x80x94CONR1R2, xe2x80x94CH2NCO, xe2x80x94CHO or xe2x80x94COOR8 where R8 is C1-4 alkyl.
The compounds of formula (II) are readily converted to compounds of formula (I) by reduction, optionally followed by alkylation. In the case of the nitriles and arnides of formula (II), the reduction is preferably carried out using a complex hydride reducing agent such as lithium aluminium hydride or sodium borohydride, whilst in the case of the isocyanates of formula (II), treatment with a concentrated mineral acid such as hydrochloric acid produces the desired conversion. The aldehydes and esters of formula (II) may be reductively aminated to the desired compounds of formula (I) by reduction to the corresponding alcohols using, for example, a complex hydride reducing agent, conversion of the alcohols to the corresponding alkyl or aryl sulphonates by reaction with an alkyl or aryl sulphonyl chloride such as methyl sulphonyl chloride or p.toluene sulphonyl chloride and reaction of the sulphonates with an amine of formula HNR1R2. Reductive amination of the aldehydes of formula (II) may also be carried out by catalytic reduction, for example by catalytic hydrogenation in the presence of an amine of formula HNR1R2.
The compounds are most conveniently prepared from the nitriles and amides of formula (II) and these are the preferred intermediates of the invention. The amides of formula (II) in which R7 is xe2x80x94CONR1R2 are novel compounds and are included as part of the present invention.
A primary amine produced by the above routes may be converted to a secondary or tertiary amine by alkylation. The alkylation may be carried out in conventional manner, for example by reductive alkylation, reaction with an alkyl halide or sulphate, reaction with an alkyl chloroformate followed by reduction of the resultant urethane, or when methylation is to be carried out, preferably by reaction with formic acidformaldehyde (Eschweiler-Clarke).
Intermediate compounds of formula (II) where R7 is xe2x80x94CN or xe2x80x94CHO can readily be prepared by a Diels-Alder reaction, by the addition of cyclopentadiene or cyclohexadiene to a compound of the formula R3CHxe2x95x90CHxe2x80x94CN or R3CHxe2x95x90CHxe2x80x94CHO, optionally employing, for example, diethylaluminium chloride as catalyst. The reaction is prolonged and has to be carried out at an elevated temperature, for example, from 100xc2x0 C. to 200xc2x0 C., especially about 160xc2x0 C., yielding bicycloheptenyl or bicyclooctenyl derivatives, which can be catalytically reduced to give the compounds of formula (II), as illustrated below. 
The reaction results in cis- and trans-enantiomers in racemic mixtures, and can be used to produce both the bicycloheptane and bicyclooctane derivatives of formula (I) above.
A reaction which can conveniently be employed to produce chiral enantiomers of the cycloheptyl derivatives utilises Evans chiral auxilliaries as, for example, oxazolidine amide intermediates of the formula: 
where R9 is alkyl, aryl or aralkyl, from the corresponding a-unsaturated acid, as follows: 
followed by a Diels-Alder reaction with cyclopentadiene in the presence of a Lewis acid and solvent such as dichloromethane, at a low temperature for example between xe2x88x9210xc2x0 C. and xe2x88x9230xc2x0 C. The reaction proceeds readily to give a bicycloheptenyl derivative, which on reduction yields the compound of formula (IV) above, as follows: 
Alternatively, the intermediates of formula (V) can be prepared (1) by reaction of an acryloyloxazolidine with the appropriately saturated R3 leaving species such as an R3 halide, in the presence of PdO, or (2) by reaction of an oxazolidinyl phosphonium halide with the appropriate aldehyde of formula R3CHO in the presence of a base such as triethylamine.
Alternatively, instead of employing a chiral compound of formula (IV), an oxazolidine compound in which R9 is hydrogen can be used, together with a chiral catalyst.
The compound of formula (IV) is readily converted by action of lithium hydroxide and hydrogen peroxide to the free acid, which on reaction with amine and further reduction yields a compound of formula (I), as follows. 
Choice of the appropriate xcex1-unsaturated acid starting material allows the production of enantiomerically pure cis- and trans-isomers.
It will be appreciated that substituents on the naphthyl or heterocyclyl ring can be introduced at the outset, or in the final stages of the synthesis. Sometimes it will be convenient to convert one substituent to another as, for example, C1-4 alkoxy to hydroxy, at an intermediate stage or in the final product.
As mentioned above, the compounds of the invention and their pharmaceutically acceptable salts have useful central nervous system activity. The compounds inhibit the uptake of neurotransmitters such as serotonin, dopamine and noradrenalin. They are surprisingly effective serotonin reuptake inhibitors, as evidenced by their displacement of [3H] citalopram at the binding sites on membranes derived from rat cortex, as in the test described below (see Example 23). In a similar test, also employing rat cortex membrane, the compounds displaced nisoxetine, demonstrating their ability to inhibit noradrenalin reuptake, see Journal of Pharmacology and Experimental Therapeutics Vol. 272, No. 3, 1176-1186, 1995. The dopamine reuptake properties of the compounds of the invention are demonstrated in the test described in Molecular Pharmacology 45: 125-135, using membranes derived from rat striatum. In this test displacement of WIN 35,428 from its reuptake site, is measured.
Because of their profile of neurotransmitter reuptake properties, the compounds of the present invention are indicated for use in treating a variety of conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, senile dementia, Alzheimer""s, memory loss, attention-deficit hyperactivity disorder, sexual dysfunction, Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders, obsessive compulsive disorder, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction including cocaine abuse, emesis and sleep disorders.
The compounds of the invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall within the range of 0.01 to 20 mgkg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used.
The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
Accordingly the invention includes a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, associated with a pharmaceutically acceptable excipient. In making the compositions of the invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The excipient may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate or oil. The compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
Depending on the route of administration, the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories. Preferably the compositions are formulated in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.